Ischemic heart and vascular diseases are the leading cause of death worldwide, accounting for more than 7 million deaths globally and 1 in 5 deaths in Singapore each year1. Diseases, such as myocardial infarction, stroke and limb ischemia, occur due to blockage of arteries and reduced blood supply to heart muscle, brain, and limb, respectively. Novel pro-angiogenic treatments aimed at developing collateral blood flow to limit tissue damage following an ischemic event have attracted much attention2,3. Angiogenesis is principally mediated by growth factors, most notably VEGF (in particular the VEGF165 isoform) that exerts angiogenic activity by binding and activating VEGF receptor 2, one of the two transmembrane receptor tyrosine kinases expressed on blood endothelial cells; so triggering downstream mitogen-activated signals4-7. Due to its potent pro-angiogenic effects, VEGF has been trialled in clinical applications, but the outcomes have so far been disappointing2,3,8. The major obstacle is that this soluble peptide growth factor is unstable in physiological environments and rapidly degrades, and has to be administered at high (and excessive) dose that causes unwanted side effects. It is also expensive to produce. As such, an effective, stable, and less expensive medication is in high demand to achieve more rapid and successful restoration of blood supply to degenerative sites.
Whilst pro-angiogenesis therapies hold great promise for treating myocardial infarction, limb and other ischemic vascular diseases with high mortality, VEGF therapy for the treatment of ischemic disease has been questioned as therapeutic concentrations of soluble proteins are difficult to maintain at ischemic sites, and exogenous growth factors easily lose activity while being overdosed. Thus, new, effective, stable and cheaper medication for accomplishing VEGF-mediated angiogenesis is required.
The biomedical community has recently discovered the importance of HS and its pro-angiogenic action with VEGF. HS is a variably sulfated, linear polysaccharide composed of repeating disaccharide units of glucoronic acid (GlcA) and glucosamine (GlcN), and plays essential roles in controlling cell phenotype and tissue development9,10. Certain HS species, together with the likes of neuropillin-1, are required to form a complex with VEGF ligand and receptor to stabilise and enhance the VEGF165-VEGFR2 interaction4. Specifically, HS binds to the 55-residue COOH-terminal amino acid sequence of VEGF165, and regulates VEGF165-mediated endothelial proliferation, tube formation, as well as vascular hyperpermeability5,6. In combination with polymer-based biomaterials, heparin has shown favourable ability in maintaining a sustained release of VEGF and producing localised vascularisation11,12. However, heparin is not suitable to stimulating angiogenesis in clinical applications. First, this highly charged HS species has notable anti-coagulant effects that cause serious adverse events such as haemorrhage (bleeding), thrombocytopenia, and hyperkalemia13,14. Overdoses of heparin have also been reported and are fatal15. Second, instead of selectively binding pro-angiogenic factors, heparin and mixtures of HS variants ubiquitously bind a variety of other soluble growth factors; given their inherent lack of specificity. Some of these nonspecific bindings may bring forward unpredictable effects that may antagonise the fundamental process needed for controlled angiogenesis.